title: CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer.
abstract: The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ling
authors.forename: Riccardo
authors.initials: R
authors.lastname: Spizzo
authors.forename: Yaser
authors.initials: Y
authors.lastname: Atlasi
authors.forename: Milena
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authors.lastname: Nicoloso
authors.forename: Masayoshi
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authors.forename: Roxana S
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authors.forename: Roberta
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authors.lastname: De Vries
authors.forename: Xinna
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authors.lastname: Zhang
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authors.lastname: Ferracin
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authors.forename: Janneke F
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authors.lastname: van Galen
authors.forename: Berna H
authors.initials: BH
authors.lastname: Beverloo
authors.forename: Maryam
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authors.lastname: Shariati
authors.forename: Franziska
authors.initials: F
authors.lastname: Haderk
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Estecio
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Gijs A
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authors.lastname: Patijn
authors.forename: David C
authors.initials: DC
authors.lastname: Gotley
authors.forename: Vikas
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authors.forename: Imad
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authors.forename: Subrata
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authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.forename: James
authors.initials: J
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authors.forename: Ken
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authors.forename: Itsuki
authors.initials: I
authors.lastname: Taniguchi
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Song
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Stephen N
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authors.lastname: Thibodeau
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Maarit
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authors.lastname: Tiirikainen
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.forename: Koshi
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authors.lastname: Mimori
authors.forename: Masaki
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authors.lastname: Mori
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: Ian
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authors.lastname: Tomlinson
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Ioana
authors.initials: I
authors.lastname: Berindan-Neagoe
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lanza
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway
chemical_list: C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; C000609264:long non-coding RNA CCAT2, human